Flecainide [2,5-bis(2,2,2-trifluoroethoxy)-N-(2-piperidylmethyl)benzarnide] is an effective antiarrythnic drug that acts on the cell membrane to reduce fast inward depolarization current.
One prior art method for preparing Flecainide [IV], disclosed in British Patent Application No. 2,045,760, starts from 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid [III]. ##STR4##
Compound [III] is prepared by a multi-stage process, comprising the conversion of 1,4dibromobenzene or hydroquinone to 1,4-bis(2,2,2-trifluoroethoxy)benzene, which is acetylated to form 2,5-bis(2,2,2-trifluoroethoxy)acetophenone. The acetophenone is then oxidized to form the corresponding benzoic acid derivative, which is then converted to its acid chloride and reacted either with 2-(aminomethyl)piperidine to form the Flecainide product in one step or with 2-(aminomethyl)pyridine, followed by catalytic hydrogenation of the pyridine ring, to form Flecainide in two steps.
The one step process has a serious disadvantage in that the acid chloride reacts non-selectively with both nitrogen atoms of the 2-(aminomethyl)piperidine, resulting in a mixture of the two acylated isomers. This is the main reason why the two-step process via the pyridine intermediate is commercially preferred, A further disadvantage is due to the fact that the acid chloride intermediate disclosed in GB 2,045,760A is a liquid which cannot be stored for long periods of time, but must be used immediately after it is prepared.
Trifluoroethoxybenzoic acids of the formula [I] are useful intermediates in the pharmaceutical industry. ##STR5##
These compounds can be obtained by the reaction of hydroxybenzoic acids of the general formula [V] with 2,2,2-trifluoroethyl triflate [VI] according to Scheme 1 (Banift, E. H. etat., J Med. Chem. 18:1130 (1975)). ##STR6##
This method requires the use of trifluoroethyl triflate [VI] which is costly and not easily available commercially.
Another method (GB 2045760A) involves the oxidation of the acetyl group of trifiuoroethoxyacetophenones with hypochlorite as shown in Scheme 2. However, partial halogenation of the benzene ring may occur in this process, thus making it difficult for production of the (2,2,2-trifluoroethoxy)benzoic acids [I] as pharmaceutical precursors. ##STR7##
There is only one reported example of copper assisted fluoroalkoxy-de-halogenation of a 2-bromo-1-naphthalenecarboxylic acid derivative (Wrobel J. et al., J. Med. Chem. 34, 2504 (1991)). This example is very specific since it describes the de-halogenation of an active halogen, i.e. bromine, which is also located in a highly activated ortho position to a carboxylic group.